Genetic Variant NM_020777.3:c.50C>G (chr4-7192696-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020777.3(SORCS2):c.50C>G(p.Ala17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 988,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

SORCS2
NM_020777.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.248

Publications

0 publications found

Variant links:

Genes affected

SORCS2 (HGNC:16698): (sortilin related VPS10 domain containing receptor 2) This gene encodes one family member of vacuolar protein sorting 10 (VPS10) domain-containing receptor proteins. The VPS10 domain name comes from the yeast carboxypeptidase Y sorting receptor Vps10 protein. Members of this gene family are large with many exons but the CDS lengths are usually less than 3700 nt. Very large introns typically separate the exons encoding the VPS10 domain; the remaining exons are separated by much smaller-sized introns. These genes are strongly expressed in the central nervous system. [provided by RefSeq, Jul 2008]

SORCS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057240605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SORCS2	NM_020777.3 link	c.50C>G	p.Ala17Gly	missense_variant	Exon 1 of 27	ENST00000507866.6	NP_065828.2	Q96PQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SORCS2	ENST00000507866.6 link	c.50C>G	p.Ala17Gly	missense_variant	Exon 1 of 27	1	NM_020777.3	ENSP00000422185.2		Q96PQ0

Frequencies

GnomAD3 genomes

AF:

0.000137

AC:

AN:

146498

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000258

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000291

AC:

245

AN:

842334

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

119

AN XY:

389996

show subpopulations

African (AFR)

AF:

0.0000628

AC:

AN:

15928

American (AMR)

AF:

0.00

AC:

AN:

1310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5340

East Asian (EAS)

AF:

0.00

AC:

AN:

3884

South Asian (SAS)

AF:

0.00

AC:

AN:

17370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1644

European-Non Finnish (NFE)

AF:

0.000305

AC:

234

AN:

767910

Other (OTH)

AF:

0.000360

AC:

AN:

27786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000137

AC:

AN:

146498

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

71268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40848

American (AMR)

AF:

0.000203

AC:

AN:

14766

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3392

East Asian (EAS)

AF:

0.00

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8466

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000258

AC:

AN:

65882

Other (OTH)

AF:

0.00

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.50C>G (p.A17G) alteration is located in exon 1 (coding exon 1) of the SORCS2 gene. This alteration results from a C to G substitution at nucleotide position 50, causing the alanine (A) at amino acid position 17 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.0037

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.36

M_CAP

Benign

0.051

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

0.25

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.060

REVEL

Benign

0.032

Sift

Benign

0.60

Sift4G

Benign

0.59

Polyphen

0.0010

Vest4

0.047

MutPred

0.20

Gain of relative solvent accessibility (P = 0.0166);

MVP

0.45

MPC

1.8

ClinPred

0.024

GERP RS

1.6

PromoterAI

0.019

Neutral

(source)

Varity_R

0.045

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_020777.3:c.50C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over